This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Subproject #4: Gammaherpesvirus Latency and Immunity Scott A. Tibbetts The gamma-herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are associated with numerous malignancies in humans including lymphomas, carcinomas, and sarcomas, and are critical determinants of lymphoproliferative disease following hematopoietic stem cell transplantation. Gammaherpesviruses maintain life-long latent infection in restricted subsets of hematopoietic cells. Thus, defining cellular reservoirs that harbor latent virus and mechanisms that govern long-term infection is critical for designing rational strategies to prevent disease. In vivo studies of gammaherpesviruses in humans have been limited by the difficulties of working in the natural host. Murine gammaherpesvirus 68 (gHV68) is genetically related to EBV and KSHV and causes lymphoma and lymphoproliferative disease in mice, providing a small animal model for mechanistic in vivo studies of the virus/host relationship. Like EBV and KSHV, gHV68 latently infects peripheral B cells and other hematopoietic cells including tissue macrophages and dendritic cells. It is not understood how gammaherpesvirues gain access to these cells or how they establish latent infection. We hypothesize that the bone marrow is a reservoir for gammaherpesvirus latency and that infection of hematopoietic cells in the bone marrow facilitates chronic infection and disease. We will (i) define whether the bone marrow is a reservoir for latency, (ii) define the cell types infected in the bone marrow, and (iii) determine the role of bone marrow latency in viral dissemination and immune evasion. The long-term goal is to understand how gammaherpesviruses establish life-long latency in host immune cells and how alterations in that relationship result in the development of disease.